Professor Zhang Qingyuan: Pola's three major offensive tools (3) - crackable connectors, ADC drugs "strong and low toxicity" guarantee

Every opening of the unknown world has the brave foresight of pioneers; Every journey of sneaking in the dark night, there is a little lamp man fearlessly leading the way
.
The series of reports "Solving the Puzzle Star - Unlocking the New Standard for DLBCL Cure" digs deep into the difficult problems in the treatment of diffuse large B-cell lymphoma (DLBCL) and explores the clinical unmet needs; Combined with clinical research and Chinese and foreign real-world treatment experience, we will jointly explore a new standard
for accurate diagnosis and treatment of DLBCL.
Polatuzumab Vedotin (Pola) is transformed into Pole Star, which is guided by the biggest names in the field to help optimize diagnosis and treatment strategies to improve the survival
of DLBCL patients in China.

The series of articles "Pola's Three Offensive Tools" has analyzed the problem of Pola's payload drug MMAE through the bystander effect, which is expected to overcome the problem of tumor heterogeneity; Acts on the target of CD79b, triggers rapid endocytosis of antibodies by cancer cells, and the treatment population will be more extensive; In this issue, we will continue to explore the mysteries of Pola's treatment of DLBCL starting from the lysable connecto
.

DLBCL is highly heterogeneous, and the requirements for efficacy and safety in high-risk patients and elderly/frail patients are increased
.
Antibody drug conjugates (ADCs) have been shown to improve tumor clinical outcomes, what are the key technical considerations behind ADC drug design? What is the role of the connector, one of the three constituent elements? What role does it play in the treatment of DLBCL?

DLBCL treatment bottleneck, "efficacy" and "safety" how to choose

DLBCL is considered a curable disease, but due to the highly heterogeneous nature of DLBCL, there are significant differences
in the effectiveness of standard therapy in patients with different subtypes.
High-risk patient subtypes such as high IPI scores, activated B-cell type (ABC) subtypes, and double-expression/double-strike often have poor prognosis ^[1] and require more effective treatment regimens
.
However, due to the characteristics of many comorbidities and poor chemotherapy tolerance in the elderly/frail population, it is often necessary to sacrifice part of the efficacy to ensure safety during treatment to achieve the best benefit-risk ratio
.
How to break the current dilemma, there is an urgent need for strong and low-toxicity drugs and treatment methods
.

With the deepening of research and the continuous development of biotechnology, antibody drug conjugates (ADCs) known as "magic bullets" have entered a golden period
of development.
Currently, more than 100 ADC drug candidates are undergoing clinical trials at different stages, and more than 10 ADC drugs have been approved by the US FDA for the treatment of solid and hematologic malignancies (Figure 1) ^[2].

Figure 1 ADC drugs have entered a golden period of development

As a third-generation ADC, what are the key points of technical considerations behind the design of vipotluplizumab (Pola)? What effect will it have on the therapeutic effect of the drug? What is the role of its important component, connector-payload technology? What are the mysteries behind the crackable connectors used in more and more new ADC drugs such as Pola in recent years?

Crackable hymen, connecting "efficient" and "low-toxicity"

ADC drugs are composed of antibodies, connectors and payload small molecule toxins, which need to have sufficient stability to enable the ADC to circulate in the blood and locate to the target site without premature lysis to avoid non-specific toxicity; At the same time, after delivery to the target cell, it can be quickly lysed to release the payload and exert a killing effect
.
Hymens are divided into lysable and non-lysable types, and their structure and coupling to antibodies have important effects on the uniformity, circulatory stability, tolerability, and overall therapeutic effect of the ADC
^[3].

Vaporatizumab (Pola) is an ADC that uses MC-Val-Cit-PAB as a linker to the payload monomethylolimitin E (MMAE) to an anti-CD79b monoclonal antibody (Figure 2) ^[4].

Val-Cit (VC) is a protease lyzable hymens that are widely
used in ADCs.
VC hybrids take advantage of the differences between the tumor microenvironment and the normal physiological environment to release the payload[⁵], and are cut and degraded by histoproteinase B after reaching the tumor cells, while the pH value is high in the normal physiological environment and the histoproteinase B deficiency does not degrade in the systemic circulation ^[6], reducing off-target toxicity
.

Figure 2 Structure diagram of vipotulizumab (Pola).

It has been found that VC hyenons exhibit good performance in the delivery and release of the loaded cytotoxic drug MMAE ^[7
].
。 At present, several new ADC drugs using vc-MMAE have been approved, including the first clinically approved for the treatment of lymphoma with verbitoximab (ADC against CD30), Verdicitumab (ADC against HER2) approved for gastric cancer and urothelial cancer, Tisotumab vedotin (ADC against tissue factor [TF]) approved for cervical cancer, and Enfortumab approved for urothelial cancer vedotin (Nectin-4 anti-ADC) and so on ^[8-9
].

Whether an ADC can play a bystander effect is one of the main differences between crackable and non-cracking connectors
.
The bystander effect is important for tumors with target antigen-expressing heterogeneity ^[5], and to some extent, can help improve the treatment of
highly heterogeneous tumors such as DLBCL.

The lysable hyenon releases a neutral load, and the free MMAE surface is electrically neutral, which is easier to spread through the cell membrane from within the cell expressing the target antigen to the neighboring cells to exert the bystander effect, thereby enhancing the efficacy
of ADC tumor killing.
Non-lysable linkers are usually after the antigen-antibody complex enters the lysosomes in the cell, and the antibody is metabolized into amino acids through the proteolysis mechanism, so the active ingredient released is the complex formed by the "amino acid residue-linker-payload", which is a charged molecule, does not have cell membrane permeability, and usually does not produce a bystander effect ^[10].

Figure 3 Connectomen of ADC drugs

The antibody-linker coupling strategy adopted by ADC has a significant impact on the drug-antibody ratio (DAR) and the intermolecular uniformity of drugs, and is one of the important considerations in molecular design^[5
].
Appropriate DAR values effectively balance antitumor activity and drug clearance, and a DAR of 2-4 may be the optimal balance between titer and slow clearance ^[6
].

Early ADCs are mostly non-fixed-point conjugation, that is, the use of natural lysine or cysteine residues on the antibody as the binding site, resulting in a high degree of heterogeneity of the ADC, and poor stability is easy to lead to off-target toxicity; With the update and development of coupling technology, a new generation of fixed-point coupling technology represented by THIOMAB^TM has been developed, that is, fixed-point coupling through antibody engineering fixed-point embedded cysteine residues, which can make ADCs highly homogeneous (Figure 4) ^[2].

Figure 4 The new generation of THIOMAB^TM fixed-point coupling technology

Vapotuzumab (Pola) has an ideal DAR (mean 3.
65) through a new generation of engineered cysteine fixed-point coupling technology, which can reasonably exert drug efficacy ^[6].

Vapotuzumab (Pola) has demonstrated good efficacy and safety

In terms of clinical efficacy, the Pola-R-CHP regimen significantly improved the survival of patients with first-line DLBCL compared with the R-CHOP regimen, and the relative risk of disease progression, recurrence, and death was reduced by 27%.

For different risk factors and Asian populations, Pola-R-CHP had a more pronounced improvement in 24-month progression-free survival (PFS24) than R-CHOP (Figure 5).

Furthermore, the Pola-R-CHP group received a lower proportion of subsequent antilymphoma therapy (23 versus 30 percent) compared with R-CHOP ^[11].

Figure 5 PFS24 improvement of Pola-R-CHP compared to R-CHOP

Pola-BR significantly improved the survival benefit of patients with R/R DLBCL

The GO29365 study showed that the Pola-BR protocol significantly improved the optimal complete response rate (CR), progression-free survival (PFS), and overall survival (OS) in patients with R/R DLBCL by nearly 3 times, with an optimal CR rate of about 58% and a 58% lower risk of death compared with BR (Figure 6).

Post-event subgroup survival analysis also showed a consistent survival benefit across all clinical and biological subgroups ^[12].

Figure 6 GO29365 study: PFS, OS, best CR

In terms of safety, the POLARIX study suggests that the introduction of Pola does not increase safety risks, and the overall safety characteristics of the Pola-R-CHP group are similar to those of the control group, which is an important difference from all previous R-CHOP+X-based studies; At the same time, patients in the trial group experienced fewer adverse events (AEs) that resulted in dose reduction (Figure 7); In addition, the Pola-R-CHP group had a higher proportion of foot treatment, and a higher proportion of patients in the experimental group received 6 courses and all 8 courses of treatment than in the R-CHOP control group (Figure 8) ^[11].

Figure 7 POLARIX study: safety situation

Figure 8 POLARIX study: Proportion of foot treatment

From the perspective of hyenons, Pola maximizes the anti-tumor effect of highly cytotoxic MMAE by using lysable VC hymen, which not only effectively delivers drugs to tumor cells, but also releases transmembrane electroneutral MMAE to exert bystander killing effects
。 This design advantage is confirmed by the published POLARIX and GO29365 studies in the clinical treatment of highly heterogeneous DLBCL, helping Pola to be approved for relapsed refractory and initial treatment of DLBCL in many countries and regions around the world with breakthrough efficacy and good safety, and will soon be approved in China
.

Affiliated Cancer Hospital of Harbin Medical University

Professor Qingyuan Zhang

A large unmet need for DLBCL is the choice of regimens for high-risk patients who need higher efficacy regimens, or patients who do not meet the standard dose of therapy, how to ensure efficacy without sacrificing safety is a question
that clinicians have been thinking about 。 ADC drug vipotlizumab Pola gives a feasible choice, Pola through the lytic hybrids to combine anti-CD79b monoclonal antibody with MMAE, from the leading mechanism of action to the clinical data breakthrough efficacy and good safety point of view, but also confirms that the perfect drug design is the guarantee for successful application of DLBCL clinical treatment, helping us to be closer to
the goal of "high efficiency and low toxicity" treatment.
It is expected that the listing of Pola will be used in clinical practice as soon as possible, thereby improving the treatment level
of the overall population of DLBCL patients in China.
It is also expected that more ADCs or other high-efficiency and low-toxicity drugs will be launched to benefit more patients
.

Qingyuan Zhang, Professor

• Chief physician, second-level professor, doctoral supervisor, provincial famous teacher

• Director of Heilongjiang Institute of Cancer Prevention and Treatment

• Vice President of the Affiliated Cancer Hospital of Harbin Medical University

• Chief Scientist of Harbin Medical University

• Distinguished Professor of Star Union Program of Harbin Medical University

• He is the leader of the national key specialty of oncology

• National 100 million talents project inductees

• Young and middle-aged experts with outstanding contributions to the country

• Chairman of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association

• Vice Chairman of the Chemotherapy Professional Committee of the Chinese Anti-Cancer Association

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Puzzle Star Solution | Prof.
Zhao Weiying and Prof.
Yanyan Liu: How to break through the R/R DLBCL puzzle? Chinese and foreign experiences unlock new scenarios

Zhu Jun and Professor Guo Ye: Pola's three major offensive tools (1) - MMAE bystander effect lays the foundation for breaking through DLBCL heterogeneity

Puzzle Star Solution | Professor Ma Jun: The ultra-classical effect, the more the level of healing, 1L DLBCL treatment is ushering in a new standard

Puzzle Star Solution | Zhang Huilai, Professor Tao Rong: Pola's three major offensive tools (2) - CD79b innovative target accurate breakthrough, DLBCL's world-first "magic bullet" to lead the new channel

Puzzle Star Solution | Professor Huang Huiqiang: Pola sends charcoal in the snow to help patients with non-transplantable R/R DLBCL rekindle hope

Puzzle Star Solution | Professors Wu Depei and Zhang Xi: Concentric relay, continuing hope, innovative ADC drug Pola opens up a new pattern suitable for transplanted R/R DLBCL treatment

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